Limit of detection of troponin discharge strategy versus usual care: randomised controlled trial.

INTRODUCTION: The clinical effectiveness of a 'rule-out' acute coronary syndrome (ACS) strategy for emergency department patients with chest pain, incorporating a single undetectable high-sensitivity cardiac troponin (hs-cTn) taken at presentation, together with a non-ischaemic ECG, remains unknown. METHODS: A randomised controlled trial, across eight hospitals in the UK, aimed to establish the clinical effectiveness of an undetectable hs-cTn and ECG (limit of detection and ECG discharge (LoDED)) discharge strategy. Eligible adult patients presented with chest pain; the treating clinician intended to perform investigations to rule out an ACS; the initial ECG was non-ischaemic; and peak symptoms occurred <6 hours previously. Participants were randomised 1:1 to either the LoDED strategy or the usual rule-out strategy. The primary outcome was discharge from the hospital within 4 hours of arrival, without a major adverse cardiac event (MACE) within 30 days. RESULTS: Between June 2018 and March 2019, 632 patients were randomised; 3 were later withdrawn. Of 629 patients (age 53.8 (SD 16.1) years, 41% women), 7% had a MACE within 30 days. For the LoDED strategy, 141 of 309 (46%) patients were discharged within 4 hours, without MACE within 30 days, and for usual care, 114 of 311 (37%); pooled adjusted OR 1.58 (95% CI 0.84 to 2.98). No patient with an initial undetectable hs-cTn had a MACE within 30 days. CONCLUSION: The LoDED strategy facilitates safe early discharge in >40% of patients with chest pain. Clinical effectiveness is variable when compared with existing rule-out strategies and influenced by wider system factors. TRIAL REGISTRATION NUMBER: ISRCTN86184521.

Randomised controlled trial of the Limit of Detection of Troponin and ECG Discharge (LoDED) strategy versus usual care in adult patients with chest pain attending the emergency department: study protocol.

INTRODUCTION: Observational data suggest a single high-sensitivity troponin blood test taken at emergency department (ED) presentation could be used to rule out major adverse cardiac events (MACE) in 10%-60% of ED patients with chest pain. This is done using an 'undetectable' cut-off (the Limit of Detection: LoD). We combined the LoD cut-off with ECG findings to create the LoDED strategy. We aim to establish whether the LoDED strategy works under real-life conditions, when compared with existing strategies, in a way that is cost-effective and acceptable to patients. METHODS AND ANALYSIS: This is a parallel-group pragmatic randomised controlled trial across UK EDs. Adults presenting to ED with suspected cardiac chest pain will be randomised 1:1. Existing rule-out strategies in current use across study centres, using serial high-sensitivity troponin testing, will be compared with the LoDED strategy. The primary outcome is successful early discharge (discharge from hospital within 4 hours of arrival) without MACE occurring within 30 days. Secondary outcomes include initial length of hospital stay; comparative costs; patient satisfaction and acceptability to patients. To detect a 9% difference between the early discharge rates (assuming an 8% rate in the standard care group) with 90% power, 594 patients need to be recruited, assuming a 95% follow-up rate. ETHICS AND DISSEMINATION: The study has been approved by the Frenchay Research Ethics Committee (reference 18/SW/0038). Results will be published in an international peer-reviewed journal. Lay summaries will be made available to patients. TRIAL REGISTRATION NUMBER: ISRCTN86184521; Pre-results.

Assessment of the 2016 National Institute for Health and Care Excellence high-sensitivity troponin rule-out strategy.

OBJECTIVE: We aimed to evaluate the limit of detection of high-sensitivity troponin (hs-cTn) and Thrombolysis In Myocardial Infarction (TIMI) score combination rule-out strategy suggested within the 2016 National Institute for Health and Care Excellence (NICE) Chest Pain of Recent Onset guidelines and establish the optimal TIMI score threshold for clinical use. METHODS: A pooled analysis of adult patients presenting to the emergency department with chest pain and a non-ischaemic ECG, recruited into six prospective studies, from Australia, New Zealand and the UK. We evaluated the sensitivity of TIMI score thresholds from 0 to 2 alongside hs-cTnT or hs-cTnI for the primary outcome of major adverse cardiac events within 30 days. RESULTS: Data were available for 3159 patients for hs-cTnT and 4532 for hs-cTnI, of these 376 (11.9%) and 445 (9.8%) had major adverse cardiac events, respectively. Using a TIMI score of 0, the sensitivity for the primary outcome was 99.5% (95% CI 98.1% to 99.9%) alongside hs-cTnT and 98.9% (97.4% to 99.6%)%) alongside hs-cTnI, identifying 17.9% and 21.0% of patients as low risk, respectively. For a TIMI score ≤1 sensitivity was 98.9% (97.3% to 99.7%)%) alongside hs-cTnT and 98.4% (96.8% to 99.4%)%) alongside hs-cTnI, identifying 28.1% and 35.7% as low risk, respectively. For TIMI≤2, meta-sensitivity was <98% with either assay. CONCLUSIONS: Our findings support the rule-out strategy suggested by NICE. The TIMI score threshold suggested for clinical use is 0. The proportion of patients identified as low risk (18%-21%) and suitable for early discharge using this threshold may be sufficient to encourage change of practice. TRIAL REGISTRATION NUMBERS: ADAPT observational study/IMPACT intervention trial ACTRN12611001069943.ADAPT-ADP randomised controlled trial ACTRN12610000766011. EDACS-ADP randomised controlled trial ACTRN12613000745741. TRUST observational study ISRCTN no. 21109279.

Cost-Effectiveness Analysis of Natriuretic Peptide Testing and Specialist Management in Patients with Suspected Acute Heart Failure.

OBJECTIVES: To determine the cost-effectiveness of natriuretic peptide (NP) testing and specialist outreach in patients with acute heart failure (AHF) residing off the cardiology ward. METHODS: We used a Markov model to estimate costs and quality-adjusted life-years (QALYs) for patients presenting to hospital with suspected AHF. We examined diagnostic workup with and without the NP test in suspected new cases, and we examined the impact of specialist heart failure outreach in all suspected cases. Inputs for the model were derived from systematic reviews, the UK national heart failure audit, randomized controlled trials, expert consensus from a National Institute for Health and Care Excellence guideline development group, and a national online survey. The main benefit from specialist care (cardiology ward and specialist outreach) was the increased likelihood of discharge on disease-modifying drugs for people with left ventricular systolic dysfunction, which improve mortality and reduce re-admissions due to worsened heart failure (associated with lower utility). Costs included diagnostic investigations, admissions, pharmacological therapy, and follow-up heart failure care. RESULTS: NP testing and specialist outreach are both higher cost, higher QALY, cost-effective strategies (incremental cost-effectiveness ratios of £11,656 and £2,883 per QALY gained, respectively). Combining NP and specialist outreach is the most cost-effective strategy. This result was robust to both univariate deterministic and probabilistic sensitivity analyses. CONCLUSIONS: NP testing for the diagnostic workup of new suspected AHF is cost-effective. The use of specialist heart failure outreach for inpatients with AHF residing off the cardiology ward is cost-effective. Both interventions will help improve outcomes for this high-risk group.

Evaluation of High-Sensitivity Cardiac Troponin I Levels in Patients With Suspected Acute Coronary Syndrome.

IMPORTANCE: Low concentrations of high-sensitivity cardiac troponin I determined on presentation to the emergency department (ED) have been shown to have an excellent negative predictive value (NPV) for the identification of acute myocardial infarction. The sensitivity, and therefore clinical applicability, of such testing strategies is unknown. OBJECTIVE: To determine the diagnostic performance of low concentrations of high-sensitivity cardiac troponin I in patients with suspected cardiac chest pain and an electrocardiogram showing no ischemia as an indicator of acute myocardial infarction. DESIGN, SETTING, AND PARTICIPANTS: A pooled analysis of 5 international (Australia, New Zealand, and England) prospective, observational cohort studies with blinded outcome assessment and 30-day follow-up was conducted. A total of 3155 patients presenting with symptoms suggestive of cardiac ischemia were included in the analysis. Eligible patients had a nonischemic electrocardiogram determined and high-sensitivity troponin I measured at presentation. The lower limit of detection (1.2 ng/L) as well as cutoff concentrations rounded to the nearest integer for a high-sensitivity troponin I assay were used in the analysis. Recruitment was undertaken from November 1, 2007, to August 10, 2013. MAIN OUTCOMES AND MEASURES: The primary outcome was fatal or nonfatal acute myocardial infarction occurring within 30 days of ED presentation, adjudicated with serial troponin testing. The secondary outcome was the proportion of patients potentially suitable for early discharge at each cutoff concentration. RESULTS: Of the 3155 eligible patients, 1771 were male (56.1%), and mean (SD) age was 57.4 (13.3) years. Acute myocardial infarction developed in 291 individuals (9.2%). The 1.2-ng/L limit of detection gave a sensitivity of 99.0% (95% CI, 96.8%-99.7%) and an NPV of 99.5% (95% CI, 98.4%-99.9%). This cutoff level would allow for early discharge of 594 patients (18.8%). All higher rounded cutoff values had sensitivities less than 98.0%. Diagnostic performance of the limit of detection was maintained when patients were stratified by age, sex, risk factors, presence of coronary artery disease, and early presentation. CONCLUSIONS AND RELEVANCE: High-sensitivity troponin I concentrations determined at presentation to the ED that were below the limit of detection identified 18.8% of patients potentially suitable for discharge, with a high sensitivity for acute myocardial infarction. Rounded cutoff values above the limit of detection may not have the required sensitivity for clinical implementation.

Evaluation of a telephone advice system for remote intravenous thrombolysis in ischemic stroke: data from a United kingdom network.

BACKGROUND AND PURPOSE: There is limited evidence for remote stroke thrombolysis using telephone consultation and teleradiology. Results from a UK network using this treatment model are presented. METHODS: Retrospective study of consecutive patients thrombolysed in 5 hospitals, with well organized stroke services, between 2012 and 2013. Remote thrombolysis was compared with thrombolysis delivered in person for symptomatic intracerebral hemorrhage, death within 7 days, and 90-day modified Rankin scores. RESULTS: Of 586 patients, 220 (37.5%) were thrombolysed remotely. The 2 groups were well matched (median age 77 years, NIHSS 12). Remote thrombolysis increased treatment time by 22 minutes. Outcomes were no different in the 2 groups (remote versus standard): symptomatic intracerebral hemorrhage (3.6% versus 4.6%), death within 7 days (6.4% versus 7.1%), modified Rankin score <2 (46.0% versus 46.1%), and modified Rankin score 6 (15% versus 17.5%) at 90 days. CONCLUSION: Telephone advice and teleradiology, within an organized system of care, can be an effective method of delivery of intravenous thrombolysis.

Reducing delay to stroke thrombolysis--lessons learnt from the Stroke 90 Project.

BACKGROUND: The Stroke 90 Project was implemented to reduce delays to stroke thrombolysis and involved 7 hospitals and 2 ambulance services in the Avon, Gloucester, Wiltshire and Somerset regional network. Interventions included a direct to CT (DtoCT) protocol for paramedics to transport patients directly to the CT scanner. Coincidentally, there were severe winter pressures on all participating emergency departments during this period. METHODS: Comparison of data from 2 groups across all 7 hospitals: preintervention (n=136) and postintervention patients (n=215) thrombolysed from August 2012 to January 2013. The χ(2) test, t tests, multiple and linear regression were used for analysis. RESULTS: Ambulance transport times were 56.8 min for preintervention versus 57.5 min for postintervention patients (p=0.78). 11.7% of preintervention patients received thrombolysis within 90 min of call for help versus 23.7% of postintervention cases (p=0.0135). 44% of postintervention patients entered the DtoCT pathway and achieved a mean reduction in door to CT time of 17 min (95% CI 11.5 to 21.5; p<0.0001) and a 19 min reduction in door to needle time (95% CI 10.8 to 26.8; p<0.0001). CT to needle times were 43.8 min preintervention and 42.1 min postintervention (p=0.57). CONCLUSIONS: The DtoCT pathway was successful in reducing delays to thrombolysis and should be implemented routinely. The call to door and CT to needle times were not improved by our interventions and further work is required to streamline these. Factors beyond the control of most hospitals may play a role in delaying treatment, but local changes can be implemented to mitigate this.

A novel multipatient intranasal diamorphine spray for use in acute pain in children: pharmacovigilance data from an observational study.

OBJECTIVES: To establish the safety of an intranasal diamorphine (IND) spray in children. DESIGN: An open-label, single-dose pharmacovigilance trial. SETTING: Emergency departments in eight UK hospitals. PARTICIPANTS: Children aged 2-16 years with a fracture or other trauma. OUTCOME MEASURES: Adverse events (AE) specifically related to nasal irritation, respiratory and central nervous system depression. RESULTS: 226 patients received 0.1 mg/kg IND. No serious or severe AEs occurred. The incidence of treatment-emergent AEs (TEAEs) was 26.5% (95% CI 20.9% to 32.8%), 93% being mild. 89% were related to treatment, all being known effects of the drug or route of administration except for three events in two patients. 20.4% (95% CI 15.3% to 26.2%) patients reported nasal irritation, all mild except one moderate and one 'unknown' severity. No respiratory depression was reported. Three AEs related to reduced Glasgow Coma Score (GCS) occurred, all mild. CONCLUSIONS: There were no safety concerns raised during the conduct of the study. In addition to expected side effects, IND can cause mild nasal irritation in a proportion of patients. EUROPEAN UNION DRUG REGULATING AUTHORITIES CLINICAL TRIAL NO: 2009-014982-16.

Cost-effectiveness of presentation versus delayed troponin testing for acute myocardial infarction.

OBJECTIVES: To estimate the cost-effectiveness of delayed troponin testing for myocardial infarction compared with troponin testing at presentation. DESIGN: Decision analysis modelling of cost-effectiveness using secondary data sources. SETTING: Acute hospitals in the UK. POPULATION: Patients attending hospital with suspected myocardial infarction but a normal or non-diagnostic ECG and no major comorbidities requiring admission. INTERVENTIONS: Delayed troponin testing (10 h after symptom onset) compared with standard and high-sensitivity troponin testing at presentation and no testing. Sensitivity analysis evaluated high-sensitivity troponin testing 3 h after initial assessment. MAIN OUTCOME MEASURES: The incremental cost per quality-adjusted life year (QALY) gained by each strategy, compared with the next most effective alternative, and the probability of each strategy being cost-effective at varying willingness-to-pay per QALY gained. RESULTS: In all scenarios tested, presentation high-sensitivity troponin testing was the most effective strategy with an incremental cost-effectiveness ratio below the £20 000/QALY threshold. 10 h troponin testing was only likely to be cost-effective if a discharge decision could be made as soon as a negative result was available and the £30 000/QALY threshold was used, or if a lower sensitivity estimate for presentation high-sensitivity troponin was assumed. Sensitivity analysis showed that including high-sensitivity troponin testing at presentation and 3 h in the analysis makes this the most cost-effective strategy. CONCLUSIONS: Delayed troponin testing is unlikely to be cost-effective compared with high-sensitivity troponin testing at presentation in most scenarios. Current NICE chest pain guidelines do not promote cost-effective care.

Interhospital variation in the RATPAC trial (Randomised Assessment of Treatment using Panel Assay of Cardiac markers).

BACKGROUND: The RATPAC trial showed that using a point-of-care panel of CK-MB(mass), myoglobin and troponin at baseline and 90 min increased the proportion of patients successfully discharged home, leading to reduced median length of initial hospital stay. However, it did not change mean hospital stay and may have increased mean costs per patient. The aim of this study was to explore variation in outcome and costs between participating hospitals. METHODS: RATPAC was a pragmatic multicentre randomised controlled trial (N=2243) and economic analysis comparing diagnostic assessment using the panel to standard care for patients with acute chest pain due to suspected myocardial infarction at six hospitals. The difference in the proportion of patients successfully discharged (primary outcome) and mean costs per patient between the participating hospitals was compared. RESULTS: Point-of-care assessment led to a higher proportion of successful discharges in four hospitals, a lower proportion in one and was equivocal in another. The OR (95% CI) for the primary outcome varied from 0.12 (0.01 to 1.03) to 11.07 (6.23 to 19.66) with significant heterogeneity between the centres (p<0.001). The mean cost per patient for the intervention group ranged from being £214.49 less than the control group (-132.56 to 657.10) to £646.57 more expensive (73.12 to 1612.71), with weak evidence of heterogeneity between the centres (p=0.0803). CONCLUSION: The effect of point-of-care panel assessment on successful discharge and costs per patient varied markedly between hospitals and may depend on local protocols, staff practices and available facilities.

Intranasal diamorphine as an alternative to intramuscular morphine: pharmacokinetic and pharmacodynamic aspects.

Diamorphine is a semisynthetic derivative of morphine that is currently licensed for use in the treatment of moderate to severe acute pain, administered by the intramuscular, intravenous or subcutaneous routes. It is highly water-soluble and has a number of properties that render it suitable for administration via the nasal route. Administration via the intranasal route is well described for other drugs, but has only recently been evaluated in a clinical setting for diamorphine. A well-tolerated and rapidly effective analgesic agent has proven elusive in the paediatric setting. The pharmacokinetic profile of intranasal diamorphine in adults has been systematically studied. It is rapidly and dose-dependently absorbed as a dry powder, with peak plasma concentrations occurring within 5 minutes, and has a similar pharmacokinetic profile to that of intramuscular diamorphine. It is rapidly converted to 6-acetylmorphine (peak concentrations within 5-10 minutes) and thence to morphine (peak concentrations within 1 hour). The pharmacodynamic properties of intranasal diamorphine have also been studied in comparison with intramuscular diamorphine. Intranasal and intramuscular administration of diamorphine resulted in similar physiological responses (including pupil diameter, respiration rate and temperature). Changes in behavioural measures (including euphoria, sedation and dysphoria) were also similar. Intranasal administration of diamorphine, therefore, produces the expected drug effects on the same timescale and of the same magnitude as intramuscular injection. Intranasal diamorphine has been clinically evaluated in a randomised controlled trial versus intramuscular morphine in the setting of acute orthopaedic pain in children with fractures. Intranasal diamorphine provided the same overall degree of pain relief as intramuscular morphine, but with a quicker onset of action. It was found to be well tolerated with an acceptable safety profile. It has also been studied in the setting of patient-controlled analgesia for postoperative pain in adults, with encouraging results. The pharmacokinetic and pharmacodynamic properties of intranasal diamorphine, and particularly the ability to administer it without a needle (and therefore reduce the incidence of transmissible infection), have made this a popular route for abuse amongst opioid addicts. In this setting, however, the intranasal route is not free from adverse events, including deaths. The primary clinical need in the paediatric population is for a well tolerated, effective and expedient analgesic agent that is safe to use; intranasal diamorphine has pharmacokinetic properties that would make it suitable for such a clinical indication and, in clinical evaluations to date, appears to be promising.